Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study

Abstract

Background: The spectrum and severity of idiosyncratic drug-induced liver injury (DILI) in children are not well established.

Patients and methods: The DILIN (Drug-Induced Liver Injury Network) Prospective Study is a longitudinal multicenter study designed to determine the etiologies, risk factors, and outcomes of suspected DILI. Between September 2004 and September 2009, 30 children ages 2 to 18 years with suspected DILI who met eligibility criteria were enrolled and studied for at least 6 months.

Results: Mean age was 14 years; 70% were girls. Antimicrobial (50%) and central nervous system agents (40%) were the most commonly implicated drug classes, with minocycline (4), isoniazid (3), azithromycin (3), atomoxetine (3), and lamotrigine (3) the leading agents. Median time from drug initiation to symptom onset was 32 days. Peak (median) liver chemistries were aspartate aminotransferase 503 U/L, alanine aminotransferase 727 U/L, alkaline phosphatase 331 U/L, and total bilirubin 3.9 mg/dL. Autoantibodies were common (64%). Liver injury pattern was hepatocellular 78%, cholestatic 13%, and mixed 9%. The DILI episode was scored: mild 32%, moderate 44%, severe 20%, and fatal (within 6 months) 4%. Causality assessment was definite 36%, very likely 36%, probable 16%, possible 8%, and unlikely 4%. Seven percent had persistent liver test abnormalities at 6-month follow-up suggesting chronic DILI. Liver biopsies from 12 children most frequently demonstrated chronic hepatitis or bile duct injury.

Conclusions: Idiosyncratic DILI in children is most commonly caused by antimicrobial or central nervous system agents and usually presents with a hepatocellular injury pattern. The majority of patients recover, but morbidity and infrequent mortality are seen.

FIGURE 1

A, A 17-year-old white male taking minocycline for 2 years developed severe hepatitis. Minocycline was discontinued but then later resumed after normalization of liver biochemistries. Liver biopsy 2 months after rechallenge (ALT 628) showed moderate portal inflammation (P), interface hepatitis and scattered foci of lobular inflammation and apoptosis (arrows) (original magnification ×400). Liver dysfunction resolved with steroids. B, A 16-year-old white female developed cholestatic hepatitis 2 weeks after starting drospirenone/ethinyl estradiol birth control pills. Biopsy 4 weeks after DILI onset showed prominent canalicular cholestasis (arrows) near the central vein (V) with lobular inflammation (L) and rare apoptotic cells. Portal inflammation was also present (not shown) (original magnification ×400). C, A 10-year-old female with vanishing bile duct syndrome caused by azithromycin. Biopsy 2 weeks after DILI onset showed minimal inflammation, but most portal areas lacked bile ducts. A representative duct-less portal area is shown with portal vein (V) and hepatic artery (A) indicated (original magnification ×600).